Methods of treating developmental disorders using pipradrol

ABSTRACT

Methods of treating developmental disorders by administering a pharmaceutical composition of pipradrol or a pharmaceutically acceptable salt thereof are provided. The methods may be used to treat conditions such as epilepsy, Landau-Kleffner Syndrome, Lennox-Gastaut syndrome (LGS) and Dravet syndrome.

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims the benefit of and priority to U.S.Provisional Application Ser. No. 62/215,831, filed on Sep. 9, 2015, theentire contents of which are herein incorporated by reference.

TECHNICAL FIELD

Methods of using a composition including pipradrol, a derivativethereof, or a pharmaceutically acceptable salt thereof for the treatmentof developmental disorders in a subject in need thereof.

BACKGROUND

Pipradrol is a mild central nervous system stimulant that acts on bothdopamine and norepinephrine reuptake. It was originally marketed asMeratran® (Wm. S. Merrell Co of Cincinnati Ohio) and also in combinationwith several vitamins as Alertonic® Elixir. Pipradrol was considered an“energetic” when it first came to market in the mid to late 1950's andused for obesity, narcolepsy, and depression. Pipradrol has also beenused in the setting of obstetric and gynecological practice, withmultiple benefits, for example improving nausea and vomiting,premenstrual symptoms, post-partum psychosis, and menopausal-associateddepression Kistner and Duncan, The New England Journal of Medicine 254,507-510 (1956).

There is limited evidence that suggests pipradrol may have some efficacyin behavioral disorders in children. Oettinger, Diseases of the NervousSystem 16, 299-302 (1955). The report concludes that the action ofpipradrol lies in increasing the attention span and decreasingirritability with a resultant increase in function. However, pipradrolhas been associated with side effects such as anxiety and alertness atbedtime. Fabing, Diseases of the Nervous System 10-15 (January 1955). Inaddition, although some anticonvulsant activity has been suggested, highdoses of pipradrol may cause incoordinated activity and ataxia, followedby tremors and clonic convulsions. Following the Kefauver-Harrisamendments to the FDA act in 1962, pipradrol was one of thousands ofdrugs that were assessed by special committees to define whether therewas sufficient safety and efficacy to remain an approved drug. Thisprocess was called the Drug Efficacy Study Initiative or DESI. Thecommittee which reviewed pipradrol included the psychiatrist KarlRickels, who had published a study on 111 individuals with depression,in which pipradrol was not superior to placebo (Rickels et al., TheJournal of Clinical Pharmacology 14, 127-133; 1974). As a result,pipradrol was removed from the FDA register of approved drugs.

There remains a need for improved methods of treating developmentaldisorders including Scn1a-related disorders.

SUMMARY

Methods of treating a developmental disorder by administering to apatient in need thereof a pharmaceutical composition of pipradrol or apharmaceutically acceptable salt thereof.

In embodiments, methods are provided for treatment of developmentaldisorders including epilepsy, Landau-Kleffner Syndrome, Lennox-Gastautsyndrome (LGS) and Dravet syndrome by administering to a patient in needthereof a pharmaceutical composition of pipradrol or a pharmaceuticallyacceptable salt thereof.

In embodiments, methods are provided for treatment of developmentaldisorders including benign rolandic epilepsy (BRE), intractablechildhood epilepsy (ICE), childhood absence epilepsy (CAE), juvenilemyoclonic epilepsy (JME), infantile spasms (or West syndrome) andLennox-Gastaut syndrome (LGS) by administering to a patient in needthereof a pharmaceutical composition of pipradrol or a pharmaceuticallyacceptable salt thereof.

In embodiments, methods are provided for treatment of developmentaldisorders characterized as a sodium channel protein type 1 subunit alpha(Scn1A)-related disorder. For example, SCn1A-related disorders includegeneralized epilepsy with fibrile seizures plus, intractable childhoodepilepsy with generalized tonic-clonic seizures, intractable infantilepartial seizures, myoclonic-astatic epilepsy, severe myoclonic epilepsyin infancy, simple febrile seizures, Lennox-Gastaut syndrome (LGS),infantile spasms, and vaccine-related encephalopathy and seizures byadministering to a patient in need thereof a pharmaceutical compositionof pipradrol or a pharmaceutically acceptable salt thereof.

The methods described herein may be particularly effective in subjectsexperiencing intractable seizures, status epilepticus, akineticseizures, myoclonic seizures, absence seizures, or severe myoclonicepilepsy in infancy (SMEI).

Generally, the pipradrol or derivative thereof is administered to apatient diagnosed with a developmental disorder in a daily dosage rangeof about 0.1 mg to about 50 mg. In embodiments, an infant may beadministered pipradrol or pharmaceutically acceptable salt thereof in adaily dosage range of about 0.2 mg to about 1 mg. In embodiments, anon-infant child may be administered pipradrol or pharmaceuticallyacceptable salt thereof in a daily dosage range of about 1 mg to about 5mg. In embodiments, an adult may be administered pipradrol orpharmaceutically acceptable salt thereof in a daily dosage range ofabout 5 mg to about 10 mg.

DETAILED DESCRIPTION

Provided herein are methods and compositions for treating developmentaldisorders by administering to a patient in need thereof a pharmaceuticalcomposition comprising pipradrol, a derivative thereof, or apharmaceutically acceptable salt thereof. In embodiments, the methodsand compositions described herein include pipradrol or apharmaceutically acceptable salt thereof.

In embodiments, the methods described herein may be used to treatdevelopmental disorders including epilepsy, Landau-Kleffner Syndrome,Lennox-Gastaut syndrome (LGS) and Dravet syndrome. In embodiments, themethods include treatment of Dravet syndrome.

In embodiments, the methods described herein may be used to treatdevelopmental disorders including benign rolandic epilepsy (BRE),intractable childhood epilepsy (ICE), childhood absence epilepsy (CAE),juvenile myoclonic epilepsy (JME), infantile spasms (or West syndrome),generalized epilepsy with febrile seizure plus (GEFS+) andLennox-Gastaut syndrome (LGS).

In embodiments, the methods described herein may be used to treatdevelopmental disorders characterized as a sodium channel protein type 1subunit alpha (Scn1A)-related disorder. For example SCn1A-relateddisorders include generalized epilepsy with fibrile seizures plus,intractable childhood epilepsy with generalized tonic-clonic seizures,intractable infantile partial seizures, myoclonic-astatic epilepsy,severe myoclonic epilepsy in infancy, simple febrile seizures,Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-relatedencephalopathy and seizures.

The methods described herein may be particularly effective in subjectsexperiencing intractable seizures, status epilepticus, akineticseizures, myoclonic seizures, absence seizures, or severe myoclonicepilepsy in infancy (SMEI). In embodiments, the disorders arecharacterized by intractable seizures. Intractable seizures (alsoreferred to as “uncontrolled” or “refractory” seizures) are seizuresthat cannot be controlled with conventional treatments. For example, thesubject can have intractable epilepsy or another disorder characterizedby intractable seizures, or a disorder characterized by statusepilepticus. Status epilepticus is a condition in which seizures followone another without recovery of consciousness between them. Accordingly,in embodiments, the disclosed methods are used to treat subjects thatare resistant to one or more conventional therapies.

The methods described herein may be particularly useful for treatingchildren and infants, and for treating disorders that onset duringinfancy or childhood. In embodiments, the subject of the disclosedmethod is a newborn, a baby, a toddler, a preschooler, a school-agechild, a tween, or a teenager. In embodiments, the subject is 18 yearsold or younger, 12 years old or younger, 10 years old or younger, 8years old or younger, 6 years old or younger, 4 years old or younger, 2years old or younger, 1 year old or younger. In embodiments, the subjectis an adult that is over eighteen years old.

In embodiments, the developmental disorders are characterized byseizures associated with epilepsy. In embodiments, the seizures arenon-epileptic seizures (NES) or dissociative seizures that aredistinguished from epilepsy. Non-epileptic seizures include organicnon-epileptic seizures and psychogenic seizures.

Epilepsy is a neurological disorder that occurs when nerve cell activityin the brain becomes disrupted, leading to seizures or periods ofunusual behavior, sensations and sometimes loss of consciousness. Asubject can be said to have epilepsy when having two seizures without anobvious cause. Epilepsy can occur in both adults and children, and canbe associated with a specific syndrome. Accordingly, in embodiments, thesubject has a childhood epilepsy syndrome such as benign rolandicepilepsy (BRE), childhood absence epilepsy (CAE), juvenile myoclonicepilepsy (JME), infantile spasms (or West syndrome), or Lennox-Gastautsyndrome (LGS).

In embodiments, the subject does not experience diagnosable seizures,but exhibits subclinical electrical discharges, which refers to a highrate of seizure-like activity when their brain waves are measured withan electroencephalogram. Epileptic syndromes associated with theseseizure-like discharges include Landau-Kleffner Syndrome and ContinuousSpike-wave Activity during Slow-wave Sleep.

In embodiments, the developmental disorders treated by the methods andcompositions described herein include Scn1A-related seizure disorders.Scn1A-related seizure disorders include simple febrile seizures (FS) andgeneralized epilepsy with febrile seizures plus (GEFS+) at the mild endto Dravet syndrome and intractable childhood epilepsy with generalizedtonic-clonic seizures (ICE-GTC) at the severe end. SpecificScn1A-related seizure disorders include, but are not limited to,generalized epilepsy with fibrile seizures plus, intractable childhoodepilepsy with generalized tonic-clonic seizures, intractable infantilepartial seizures, myoclonic-astatic epilepsy, severe myoclonic epilepsyin infancy, simple febrile seizures, Lennox-Gastaut syndrome (LGS),infantile spasms, and vaccine-related encephalopathy.

In embodiments, the subject has an intellectual developmental disability(IDD) such as an Autism Spectrum Disorders (ASD). In embodiments, thesubject of the disclosed method has epilepsy and an IDD or ASD disorder.Common IDD and ASD that are comorbid with seizures and epilepsy include,but are not limited to, fragile X syndrome (FXS), Rett syndrome (RTT),Angelman syndrome, Prader-Willi syndrome, Velocardiofacial syndrome,Smith-Lemli-Opitz syndrome, neuroligin mutations and“interneuronopathies” resulting from aristaless-related homeobox,X-linked (ARX) and Nueropilin 2 (NRP2) gene mutations.

In embodiments, methods and compositions are provided for treatingdevelopmental disorders by administering to a patient in need thereof apharmaceutical composition comprising pipradrol or a pharmaceuticallyacceptable salt thereof. In embodiments, compounds structurally relatedto pipradrol or a derivative or analog thereof are administered. Suchcompounds, can include, for example, desoxypipradrol, diphenylprolinol,2-(diphenylmethyl)pyrrolidine, or pharmaceutically acceptable saltsthereof.

Pipradrol, derivatives, analogues and structurally related compoundsthereof useful in the disclosed methods includes any form of thecompounds, such as the base (zwitter ion), pharmaceutically acceptablesalts, e.g., pharmaceutically acceptable acid addition salts, hydratesor solvates of the base or salt, as well as anhydrates, and alsoamorphous, or crystalline forms.

In embodiments, deuterated pipradrol or deuterated forms of pipradrolderivatives may be used. Deuteration of pharmaceuticals to improvepharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles, hasbeen demonstrated previously with some classes of drugs. Accordingly theuse of deuterium-enriched pipradrol is contemplated and within the scopeof the methods and compositions described herein. Deuterium can beincorporated in any position in replace of hydrogen synthetically,according to the synthetic procedures known in the art. For example,deuterium may be incorporated to various positions having anexchangeable proton, such as the amine N—H, via proton-deuteriumequilibrium exchange. Thus, deuterium may be incorporated selectively ornon-selectively through methods known in the art to provide deuteriumenriched pipradrol.

Deuterium enriched pipradrol may be described by the percentage ofincorporation of deuterium at a given position in the molecule in theplace of hydrogen. For example, deuterium enrichment of 1% at a givenposition means that 1% of molecules in a given sample contain deuteriumat that specified position. The deuterium enrichment can be determinedusing conventional analytical methods, such as mass spectrometry andnuclear magnetic resonance spectroscopy. In embodiments, deuteriumenriched pipradrol means that the specified position is enriched withdeuterium above the naturally occurring distribution (i.e., above about0156%). In embodiments, deuterium enrichment is, e.g., no less thanabout 1%, no less than about 5%, no less than about 10%, no less thanabout 20%, no less than about 50%, no less than about 70%, no less thanabout 80%, no less than about 90%, or no less than about 98% ofdeuterium at a specified position. In embodiments, deuterium enrichmentmay be defined as, e.g., more than about 60%, more than about 65%, morethan about 75%, more than about 80%, more than about 85%, more thanabout 95% deuterium at a specified position.

In embodiments, the pipradrol or a pharmaceutically acceptable saltthereof may include the racemic mixture, as well as compositionsincluding each enantiomer individually. The compositions and methodscontemplated herein may provide reduced dosing frequency, reducedadverse events and/or increased efficacy compared to a racemic mixtureof pipradrol. In embodiments, compositions and methods that include eachenantiomer individually may provide reduced dosing frequency, reducedadverse events and/or increased efficacy compared to the minorenantiomer. Thus, for example, contemplated herein are compositions andmethods of treatment that provide the S enantiomer of pipradrol or apharmaceutically acceptable salt thereof that is substantially free ofthe R enantiomer. In embodiments, methods and compositions hereininclude the R enantiomer of pipradrol or a pharmaceutically acceptablesalt thereof substantially free of the S enantiomer. By “substantiallyfree” it is meant that the composition includes less than 50% of theminor enantiomer. In embodiments, the compositions and methods hereinmay include less than about, e.g., 25%, 15%, 10%, 8%, 5%, 3%, 2%, orless than 1% of the minor enantiomer.

In embodiments, the methods and compositions include (S)-pipradrol, or apharmaceutically acceptable salt thereof. In embodiments, thecompositions include more than, e.g., about 75%, about 85%, about 90%,about 95% or about 98% (S)-pipradrol. In embodiments, the compositionsinclude between, e.g., about 50% to about 75%, about 75% to about 100%,about 85% to about 100%, about 90% to about 100%, or about 95% to about100% (S)-pipradrol.

In embodiments, the methods and compositions herein include(R)-pipradrol, or a pharmaceutically acceptable salt thereof. Inembodiments, the compositions include more than, e.g., about 75%, about85%, about 90%, about 95% or about 98% (R)-pipradrol. In embodiments,the compositions include between, e.g., about 50% to about 75%, about75% to about 100%, about 85% to about 100%, about 90% to about 100%, orabout 95% to about 100% (R)-pipradrol.

In embodiments, pipradrol or a pharmaceutically acceptable salt thereofis administered at dosages ranging from about 0.001 mg/kg and about 10mg/kg of body weight of a patient in need thereof, e.g., from about 0.01mg/kg to 2.0 mg/kg at least once a day. For example, dosages may includeamounts of pipradrol or a pharmaceutically acceptable salt thereof inthe range of about, e.g., 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg,0.01 mg to 10 mg, 0.1 mg to 15 mg, 0.15 mg to 12.5 mg, or 0.2 mg to 10mg, with doses of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7mg, 0.8 mg, 0.9 mg, 1.5 mg, 1.0 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75 mg, 3mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg,7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 10 mg, 11 mg, 12 mg, 15 mg, 20 mg, 25mg, and 30 mg being specific examples of doses.

Typically, dosages of pipradrol or pharmaceutically acceptable saltsthereof are administered once or twice daily to a patient in needthereof. The methods and compositions described herein may providereduced dosing frequency and reduced adverse events and/or increasedefficacy. In embodiments, the dosage is about, e.g., 0.1-20 mg/day, or0.2-15 mg/day, or 0.5-10 mg/day, or 0.75-5 mg/day, for example 0.2mg/day, 0.5 mg/day, 0.75 mg/day, 1 mg/day, 1.5 mg/day, 2 mg/day, 3mg/day, 4 mg/day, 5 mg/day, 6 mg/day, 7 mg/day, 8 mg/day, 9 mg/day, or10 mg/day. In embodiments, pipradrol, or a derivative or analoguethereof is administered at doses of 0.2 mg to 1 mg in infants or 1-20 mgin adults, once daily.

Methods of treating developmental disorders by administering to asubject in need thereof an effective amount of pipradrol or apharmaceutically acceptable salt, derivative or analogue, or combinationthereof, are provided. An effective amount or therapeutically effectiveamount can be a dosage sufficient to treat, inhibit, or alleviate one ormore symptoms of a developmental disorder such as reducing the frequencyor severity of seizures, reducing behavior abnormalities (or otherwiseimproving behavior); or to provide a desired pharmacologic and/orphysiologic effect, for example, reducing, inhibiting, or reversing oneor more of the underlying pathophysiological mechanisms underlying theneurological dysfunction, increasing dopamine levels or signaling, or acombination thereof. The precise dosage will vary according to a varietyof factors such as subject-dependent variables (e.g., age, immune systemhealth, clinical symptoms etc.).

In embodiments, the methods described herein are effective to reduce,delay, or prevent one or more other clinical symptoms of a developmentaldisorder, particularly epilepsy or Dravet syndrome. For example, theeffect of a composition including pipradrol or a pharmaceuticallyacceptable salt, derivative or analogue thereof on a particular symptom,pharmacologic, or physiologic indicator can be compared to an untreatedsubject, or the condition of the subject prior to treatment. Inembodiments, the symptom, pharmacologic, and/or physiologic indicator ismeasured in a subject prior to treatment, and again one or more timesafter treatment is initiated. In embodiments, the control is a referencelevel, or average determined based on measuring the symptom,pharmacologic, or physiologic indicator in one or more subjects that donot have the disease or condition to be treated (e.g., healthysubjects). In embodiments, the effect of the treatment is compared to aconventional treatment that is known the art.

Pipradrol or a pharamaceutically acceptable salt, derivative or analoguethereof as described herein may be considered stimulants because they“stimulate” motor behavior. These effects may come at a cost, since, incertain instances, stimulants can increase agitation and anxiety, reducesleep, and inhibit appetite. Moreover, many can be addictive and haveabuse potential. At higher doses stimulants may induce convulsions. Onthe simplest level, a stimulant may be considered to be the opposite ofa depressant, and depressants, such as barbiturates and benzodiazepineswhich may have robust anti-epileptic activity. Therefore, it is commonlybelieved that certain stimulants can be pro-convulsant and may typicallybe considered as contraindicated in the treatment of developmentaldisorders. Indeed, there is some clinical evidence that certainstimulants may lower the convulsive threshold in patients with priorhistory of seizures, in patients with prior electroencephalogram (EEG)abnormalities in the absence of seizures, and, rarely, in patientswithout a history of seizures and no prior EEG evidence of seizures.Accordingly, the methods and compositions described herein maysurprisingly provide reduction in the frequency of seizures, theseverity of seizures, or a combination thereof in a patient diagnosedwith a developmental disorder.

In embodiments, compositions and methods of treatment are provided withlow dosages of pipradrol such that the patient is provided one or morebeneficial effects related to a developmental disorder, such as, reducedseizure activity, reduced fatigue, increased mood, increasedconcentration, increased behavioral control and/or increased cognitiveability. Pipradrol is known to have a relatively long half-life that maylead to prolonged effects and drug accumulation in a patient. Providedherein are dosing regimens that allow effective treatment of adevelopmental disorder with potentially limited or substantially fewnegative side effects, e.g., convulsions and/or sleep disruption.Accordingly, the methods described herein may provide treatment of adevelopment disorder that may be considered surprising and unexpected.For example, methods are provided herein of treating developmentaldisorders in a patient in need thereof which may not cause sleepdisruption. In embodiments, methods described herein may provideeffective treatment of a development disorder without interrupting SlowWave Sleep. In embodiments methods of treating a developmental disorderwithout causing insomnia or trouble falling asleep are provided.

The methods provided may also surprisingly and unexpectedly reduce orprevent seizures, or symptoms thereof in a subject in need thereof. Themethods provided may reduce or prevent one or more different types ofseizures. Generally, a seizure can include convulsions, repetitivemovements, unusual sensations, and combinations thereof. Seizures can becategorized as focal seizures (also referred to as partial seizures) andgeneralized seizures. Focal seizures affect only one side of the brain,while generalized seizures affect both sides of the brain. Specifictypes of focal seizures include simple focal seizures, complex focalseizures, and secondarily generalized seizures. Simple focal seizurescan be restricted or focused on a particular lobe (e.g., temporal lobe,frontal lobe, parietal lobe, or occipital lobe). Complex focal seizuresgenerally affect a larger part of one hemisphere than simple focalseizures, but commonly originate in the temporal lobe or the frontallobe. When a focal seizure spreads from one side (hemisphere) to bothsides of the brain, the seizure is referred to as a secondarilygeneralized seizure. Specific types of generalized seizures includeabsences (also referred to as petit mal seizures), tonic seizures,atonic seizures, myoclonic seizures, tonic clonic seizures (alsoreferred to as grand mal seizures), and clonic seizures.

In embodiments, methods described herein may reduce the frequency ofseizures, reduce the severity of seizures, change the type of seizures(e.g., from a more severe type to a less severe type), or a combinationthereof in a subject after treatment compared to the absence oftreatment (e.g., before treatment), or compared to treatment with analternative conventional treatment.

It is believed that the disclosed compounds, such as pipradrol,pharmaceutically acceptable salts, derivatives and/or analogues thereof,can be used as a monotherapy as the only active agent. In embodiments,methods are provided of treating development disorders using pipradrolor a pharmaceutically acceptable salt thereof in a pharmaceuticallyacceptable carrier. In embodiments, methods of treating developmentdisorders include administration of pipradrol, pharmaceuticallyacceptable salts, derivatives and/or analogues thereof in combinationwith one or more other active compounds. The combination therapies caninclude administration of the active agents together in the sameadmixture, or in separate admixtures. In embodiments, the pharmaceuticalcomposition includes two, three, or more active agents. In embodiments,the combinations result in a more than additive effect on the treatmentof the disease or disorder. Thus, treatment is provided of adevelopmental disorder with a combination of agents that combined, mayprovide a synergistic effect that enhances efficacy.

In embodiments, the compound is administered in combination withconventional therapy for seizures, epilepsy, or one of the otherdisorders disclosed herein. For example, common conventional therapiesfor seizures and epilepsy include antiepileptic drugs andnon-antiepileptic drug treatments such as low carbohydrate diet (e.g.,ketogenic diets, such as classical diet, medium chain triglyceride (MCT)diet, modified Atkins diet (MAD), and low glycemic index treatment(LGIT)), intravenous immunoglobulin, steroids, elimination diet, valgusnerve stimulation, corticetomy, and multiple subpial transections.

Common antiepileptic and anticonvulsive active compounds that may beused in combination with pipradrol include, but are not limited to,acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepineacetate, ethosuximide, gabapentin, lacosamide, lamotrigine,levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam,phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide,sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, andzonisamide.

In embodiments, the disclosed methods include administering to a subjectpipradrol in combination with gaboxadol. Gaboxadol, derivatives,analogues and structurally related compounds thereof useful in thedisclosed methods includes any form of the compounds, such as the base(zwitterion), pharmaceutically acceptable salts, e.g., pharmaceuticallyacceptable acid addition salts, hydrates or solvates of the base orsalt, as well as anhydrates, and also amorphous, or crystalline forms.In embodiments, a co-therapy of pipradrol or a derivative thereof andgaboxadol or a derivative thereof is effective to reduce seizurefrequency or severity in the subject greater than either compound isadministered alone. In embodiments, the co-therapy produces a more thanadditive result compared to compounds administered individually.

In general, by way of example, dosage forms useful in the disclosedmethods can include doses of gaboxadol, derivatives, analogues andstructurally related compounds thereof in the range of 0.1 to 20 mg, 1to 15 mg, 5 to 20 mg, 7.5 to 25 mg, or 10 to 30 mg, or 12.5 to 20 mg, or15 to 25 mg, or 10 to 40 mg, or 5 to 50 mg, or 22.5 to 60 mg, or 25 to50 mg, with doses of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 75 mg, and 100 mg. Typically,such dosages are administered once, twice, or three times daily, orevery other day to, e.g., a human.

An exemplary oral dose form may include from about 2.5 mg to about 30 mggaboxadol. In embodiments, gaboxadol is in a crystalline form. Inembodiments of the medicament may include an effective amount ofgaboxadol from 2.5 mg to 20 mg, such as 2.5 mg to 4 mg, 4 mg to 6 mg, 6mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16mg, 16 mg to 18 mg, or 18 mg to 20 mg, e.g. 2.5 mg, 5 mg, 7.5 mg, 10 mg,12.5 mg, 15 mg, 17.5 mg, or 20 mg. An exemplary embodiment may includeabout 5 mg to about 20 mg of crystalline gaboxadol, such as thehydrochloride of gaboxadol. In embodiments, the total amountadministered to a subject in 24-hour period is 1 mg to 50 mg. Inembodiments, the subject may be started at a low dose and the dosage isescalated. In this manner, it can be determined if the drug is welltolerated in the subject. Dosages can be lower for children than foradults.

In embodiments, such as combination therapies, a dose of gaboxadol forchildren can be 0.1 mg/kg to 1 mg/kg, and the dose for pipradrol may be0.01 mg/kg to 0.1 mg/kg. The weight/weight ratio of gaboxadol andpipradrol is can be 10-to-1. However, the dosing ratio based onmilligrams of active pharmaceutical ingredient (API) can range from0.1-to-1 to 100-to-1 of gaboxadol-to-pipradrol respectively.

Effective treatment of a developmental disorder (e.g., SMEI or Dravetsyndrome) herein may be established by showing reduction in thefrequency of seizures (e.g., more than 50%) after a period of timecompared with baseline. For example, after a baseline period of 1 month,the patients may be randomly allocated pipradrol or placebo as add-ontherapy to standard therapies, such as valproate and clobazam, during adouble-blind period of 2 months. Primary outcome measurements mayinclude the percentage of responders on pipradrol and on placebo,defined as having experienced at least a 50% reduction of clonic (ortonic-clonic) seizure frequency during the second month of thedouble-blind period compared with baseline. Patients who present withstatus epilepticus during the double-blind period may be regarded asnon-responders. Secondary outcomes may include the absolute count ofclonic (or tonic-clonic) seizures during the second month of thedouble-blind period (normalized to 30 days, by dividing the raw count bythe exact number of days of observation and multiplying by 30) and thepercentage of change from baseline.

The effectiveness of pipradrol for the treatment of a discloseddevelopmental disorder, e.g., associated with Lennox-Gastaut syndrome,may be established in other controlled studies. For example, arandomized, double-blind, placebo-controlled study consisting of a4-week baseline period followed by a 3-week titration period and 12-weekmaintenance period may be used in patients age 2-54 years with a currentor prior diagnosis of LGS. Multiple target maintenance doses ofpipradrol may be tested according to patient body weight and specificdosing regime. A primary efficacy measure may include the percentreduction in the weekly frequency of drop seizures (atonic, tonic, ormyoclonic), also known as drop attacks, from the 4-week baseline periodto 12-week maintenance period. Thus, efficacy may be measured aspercentage reduction in weekly seizure (e.g., atonic, tonic, ormyoclonic) frequency from baseline of, e.g., 0 to <20, 20 to <40, 40 to<60, 60 to <80, 80 to <100.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosure herein belongs.

The term “about” or “approximately” as used herein means within anacceptable error range for the particular value as determined by one ofordinary skill in the art, which will depend in part on how the value ismeasured or determined, i.e., the limitations of the measurement system.For example, “about” can mean within 3 or more than 3 standarddeviations, per the practice in the art. Alternatively, “about” can meana range of up to 20%, preferably up to 10%, more preferably up to 5%,and more preferably still up to 1% of a given value. Alternatively,particularly with respect to biological systems or processes, the termcan mean within an order of magnitude, preferably within 5-fold, andmore preferably within 2-fold, of a value.

As used herein, the term “treating” or “treatment” refers toalleviating, attenuating or delaying the appearance of clinical symptomsof a disease or condition in a subject that may be afflicted with orpredisposed to the disease or condition, but does not yet experience ordisplay clinical or subclinical symptoms of the disease or condition. Inembodiments, treating” or “treatment” may refer to preventing theappearance of clinical symptoms of a disease or condition in a subjectthat may be afflicted with or predisposed to the disease or condition,but does not yet experience or display clinical or subclinical symptomsof the disease or condition. “Treating” or “treatment” may also refer toinhibiting the disease or condition, e.g., arresting or reducing itsdevelopment or at least one clinical or subclinical symptom thereof.“Treating” or “treatment” further refers to relieving the disease orcondition, e.g., causing regression of the disease or condition or atleast one of its clinical or subclinical symptoms. The benefit to asubject to be treated may be statistically significant, mathematicallysignificant, or at least perceptible to the subject and/or thephysician. Nonetheless, prophylactic (preventive) and therapeutictreatment are two separate embodiments of the disclosure herein.

“Effective amount” or “therapeutically effective amount” means a dosagesufficient to alleviate one or more symptom of a disorder, disease, orcondition being treated, or to otherwise provide a desiredpharmacological and/or physiologic effect.

“Pharmaceutically acceptable” refers to molecular entities andcompositions that are “generally regarded as safe”—e.g., that arephysiologically tolerable and do not typically produce an allergic orsimilar untoward reaction, such as gastric upset and the like, whenadministered to a human. In embodiments, this term refers to molecularentities and compositions approved by a regulatory agency of the federalor a state government, as the GRAS list under section 204(s) and 409 ofthe Federal Food, Drug and Cosmetic Act, that is subject to premarketreview and approval by the FDA or similar lists, the U.S. Pharmacopeiaor another generally recognized pharmacopeia for use in animals, andmore particularly in humans.

As used herein, the term “prevention” or “preventing” means toadminister a composition to a subject or a system at risk for or havinga predisposition for one or more symptoms caused by a disease ordisorder to facilitate cessation of a particular symptom of the diseaseor disorder, a reduction or prevention of one or more symptoms of thedisease or disorder, a reduction in the severity of the disease ordisorder, the complete ablation of the disease or disorder,stabilization or delay of the development or progression of the diseaseor disorder.

“Prodrug”, as used herein, refers to a pharmacological substance (drug)that is administered to a subject in an inactive (or significantly lessactive) form. Once administered, the prodrug is metabolized in the body(in vivo) into a compound having the desired pharmacological activity.

“Analog” and “Derivative” are used herein interchangeably and refer to acompound that possesses the same core as the parent compound, but maydiffer from the parent compound in bond order, the absence or presenceof one or more atoms and/or groups of atoms, and combinations thereof.The derivative can differ from the parent compound, for example, in oneor more substituents present on the core, which may include one or moreatoms, functional groups, or substructures. In general, a derivative canbe imagined to be formed, at least theoretically, from the parentcompound via chemical and/or physical processes.

“Stereoisomer”, as used herein, refers to isomeric molecules that havethe same molecular formula and sequence of bonded atoms (constitution),but which differ in the three dimensional orientations of their atoms inspace. Examples of stereoisomers include enantiomers and diastereomers.As used herein, an enantiomer refers to one of the two mirror-imageforms of an optically active or chiral molecule. Diastereomers (ordiastereoisomers) are stereoisomers that are not enantiomers(non-superimposable mirror images of each other). Chiral moleculescontain a chiral center, also referred to as a stereocenter orstereogenic center, which is any point, though not necessarily an atom,in a molecule bearing groups such that an interchanging of any twogroups leads to a stereoisomer. In organic compounds, the chiral centeris typically a carbon, phosphorus or sulfur atom, though it is alsopossible for other atoms to be stereocenters in organic and inorganiccompounds. A molecule can have multiple stereocenters, giving it manystereoisomers. In compounds whose stereoisomerism is due to tetrahedralstereogenic centers (e.g., tetrahedral carbon), the total number ofhypothetically possible stereoisomers will not exceed 2 n, where n isthe number of tetrahedral stereocenters. Molecules with symmetryfrequently have fewer than the maximum possible number of stereoisomers.A 50:50 mixture of enantiomers is referred to as a racemic mixture.Alternatively, a mixture of enantiomers can be enantiomerically enrichedso that one enantiomer is present in an amount greater than 50%.Enantiomers and/or diasteromers can be resolved or separated usingtechniques known in the art. “Chirality” also includes axial and planarchirality.

The term “pharmaceutically acceptable salt”, as used herein, refers toderivatives of the compounds defined herein, wherein the parent compoundis modified by making acid or base salts thereof. Example ofpharmaceutically acceptable salts include but are not limited to mineralor organic acid salts of basic residues such as amines; and alkali ororganic salts of acidic residues such as carboxylic acids. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. Suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric acids; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,tolunesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic,oxalic, and isethionic salts.

The pharmaceutically acceptable salts of the compounds can besynthesized from the parent compound, which contains a basic or acidicmoiety, by conventional chemical methods.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to theembodiments described herein. Such equivalents are intended to beencompassed by the following claims.

What is claimed is:
 1. A method of treating Dravet syndrome comprisingadministering to a patient in need thereof a pharmaceutical compositioncomprising about 0.1 mg to about 50 mg pipradrol or a pharmaceuticallyacceptable salt thereof.
 2. The method of claim 1 wherein thecomposition provides reduction in the frequency of seizures, theseverity of seizures, or a combination thereof in a patient diagnosedwith Dravet syndrome.
 3. The method of claim 1 wherein the compound isadministered to the patient a daily dosage in the range of about 0.1 mgto about 50 mg pipradrol or a pharmaceutically acceptable salt thereof.4. The method of claim 1 further comprising administering a secondcompound selected from the group consisting of gaboxadol, acetazolamide,carbamazepine, clobazam, clonazepam, eslicarbazepine acetate,ethosuximide, gabapentin, lacosamide, lamotrigine, leviteracetam,nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital,phenytoin, pregabalin, primidone, retigabine, rufinamide, sodiumvalproate, stiripentol, tiagabine, topiramate, vigabatrin, andzonisamide.